Korean J Physiol Pharmacol.  2024 Jan;28(1):31-38. 10.4196/kjpp.2024.28.1.31.

Lithium and exercise ameliorate insulin-deficient hyperglycemia by independently attenuating pancreatic α-cell mass and hepatic gluconeogenesis

• Jung SR
• Lee JH
• Ryu H
• Gao Y
• Lee J

• KMID: 2550286
• DOI: http://doi.org/10.4196/kjpp.2024.28.1.31

Abstract

As in type 1 diabetes, the loss of pancreatic β-cells leads to insulin deficiency and the subsequent development of hyperglycemia. Exercise has been proposed as a viable remedy for hyperglycemia. Lithium, which has been used as a treatment for bipolar disorder, has also been shown to improve glucose homeostasis under the conditions of obesity and type 2 diabetes by enhancing the effects of exercise on the skeletal muscles. In this study, we demonstrated that unlike in obesity and type 2 diabetic conditions, under the condition of insulin-deficient type 1 diabetes, lithium administration attenuated pancreatic a-cell mass without altering insulin-secreting β-cell mass, implying a selective impact on glucagon production. Additionally, we also documented that lithium downregulated the hepatic gluconeogenic program by decreasing G6Pase protein levels and upregulating AMPK activity. These findings suggest that lithium’s effect on glucose metabolism in type 1 diabetes is mediated through a different mechanism than those associated with exerciseinduced metabolic changes in the muscle. Therefore, our research presents the novel therapeutic potential of lithium in the treatment of type 1 diabetes, which can be utilized along with insulin and independently of exercise.

Keyword

Diabetes mellitus, type 1; Exercise; Glucagon-secreting cells; Gluconeogenesis; Lithium

Figure

• 

  Fig. 1 Lithium and exercise ameliorated hyperglycemia in insulin-deficient diabetes induced by streptozotocin (STZ). (A) Weekly body weight measurements of mice with STZ-induced hyperglycemia after lithium and/or exercise administration. (B, C) Final body weight (B) or blood glucose (C) of type 1 diabetic mice after 12 weeks of lithium and/or exercise introduction. The detailed experiment procedures are in the method section. Data are presented as means ± S.E.M. NC, saline-received normal glycemic group; PC, STZ-induced hyperglycemic group; Li, lithium(Li)-administration to STZ-received mice; Ex, moderate exercise training to STZ-received mice; Li + Ex, co-administration of Li and exercise to STZ-received mice. *p < 0.05, **p < 0.01, ***p < 0.001.

• 

  Fig. 2 Lithium and exercise attenuated pancreatic α-cell mass without changing β-cell mass and blood insulin levels. (A) Final blood insulin levels of type 1 diabetic mice after 12 weeks of lithium and/or exercise administration. (B, C) Representative images of pancreatic islets with insulin- and glucagon-positive cells labeled via immunofluorescence (B) and a quantified potion of glucagon-positive (GCG+) areas in the islets (C) (Scale bars = 100 µm). The detailed experiment procedures are in the method section. Data are presented as means ± S.E.M. NC, saline-received normal glycemic group; PC, streptozotocin (STZ)-induced hyperglycemic group; Li, lithium(Li)-administration to STZ-received mice; Ex, moderate exercise training to STZ-received mice; Li + Ex, co-administration of Li and exercise to STZ-received mice. *p < 0.05, ***p < 0.001.

• 

  Fig. 3 Lithium exhibited limited influences on exercise-mediated insulin signaling, glucose uptake, and glycogen breakdown in type 1 diabetic skeletal muscle. (A–E) Immunoblot for the indicated proteins (A) and a plot of their quantified results (B–E) of the skeletal muscle samples from type 1 diabetic mice after 12 weeks of lithium and/or exercise administration. The protein levels of Glut4 (B) and RAB10 (C), the ratio of phosphorylated Akt to total Akt (D), and the ratio of phosphorylated GSKβ to total GSKβ (E). The detailed experiment procedures are in the method section. Data are presented as means ± S.E.M. NC, saline-received normal glycemic group; PC, streptozotocin (STZ)-induced hyperglycemic group; Li, lithium(Li)-administration to STZ-received mice; Ex, moderate exercise training to STZ-received mice; Li + Ex, co-administration of Li and exercise to STZ-received mice. *p < 0.05, **p < 0.01.

• 

  Fig. 4 Lithium, independently of exercise, attenuated hepatic gluconeogenesis in type 1 diabetes. (A–E) Immunoblot for the indicated proteins (A) and their quantified results (B–E) of the liver samples from STZ-treated mice after 12 weeks of lithium and/or exercise administration. The protein levels of G6Pase (B) and PEPCK (C), the ratio of phosphorylated AMPK to total AMPK (D), and the ratio of phosphorylated p38MAPK to total p38MAPK (E). The detailed experiment procedures are in the method section. Data are presented as means ± S.E.M. NC, saline-received normal glycemic group; PC, streptozotocin (STZ)-induced hyperglycemic group; Li, lithium(Li)-administration to STZ-received mice; Ex, moderate exercise training to STZ-received mice; Li + Ex, co-administration of Li and exercise to STZ-received mice. *p < 0.05, **p < 0.01.

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